A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of janus kinase 2 for use in anticancer therapy: Discovery of CEP-33779

Journal of Medicinal Chemistry

Volumn 55, Issue 11, 2012, Pages 5243-5254

  Dugan, Benjamin J ^a   Gingrich, Diane E ^a   Mesaros, Eugen F ^a   Milkiewicz, Karen L ^a   Curry, Matthew A ^a   Zulli, Allison L ^a   Dobrzanski, Pawel ^a   Serdikoff, Cynthia ^a   Jan, Mahfuza ^a   Angeles, Thelma S ^a   Albom, Mark S ^a   Mason, Jennifer L ^a   Aimone, Lisa D ^a   Meyer, Sheryl L ^a   Huang, Zeqi ^a   Wells Knecht, Kevin J ^a   Ator, Mark A ^a   Ruggeri, Bruce A ^a   Dorsey, Bruce D ^a  

^a CEPHALON INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(3 METHANESULFONYL PHENYL) [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] AMINE; (4 METHANESULFONYL PHENYL) [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] AMINE; 8 (3 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL AMINE; 8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL AMINE HYDROCHLORIDE; 8 (4 TRIFLUOROMETHYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL AMINE; 8 (6 METHOXY PYRIDIN 3 YL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL AMINE; 8 PYRIDIN 3 YL [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YLAMINE; 8 PYRIDIN 4 YL [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YLAMINE; [3 (4 METHYL PIPERAZIN 1 YL) PHENYL] [8 (4 TRIFLUOROMETHYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] AMINE; [3 (4 METHYL PIPERAZIN 1 YL) PHENYL] [8 [4 (PROPANE 2 SULFONYL) PHENYL] [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] AMINE; [8 (2 METHOXY PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] PHENYL AMINE; [8 (3 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] PHENYL AMINE; [8 (4 FLUORO PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] [3 (4 METHYL PIPERAZIN 1 YL) PHENYL] AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] (2 METHOXY PHENYL) AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] (3 METHOXY PHENYL) AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] (3 MORPHOLIN 4 YL PHENYL) AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] (4 METHOXY PHENYL) AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] (4 MORPHOLIN 4 YL PHENYL) AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] [3 (1 METHYL PIPERIDIN 4 YL) PHENYL] AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] [3 (4 METHYL PIPERAZIN 1 YL) PHENYL] AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] [3 (4 METHYL PIPERAZIN 1 YLMETHYL) PHENYL] AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] [3 (4 MORPHOLIN 4 YL PIPERIDIN 1 YL) PHENYL] AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] [3 [4 (4 METHYL PIPERAZIN 1 YL) PIPERIDIN 1 YL] PHENYL] AMINE; [8 (4 METHANESULFONYL PHENYL) [1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 YL] PHENYL AMINE; [8 [4 (DIMETHYL PHOSPHINOYL) PHENYL] [1,2,4]TRIAZOLO[1,5 A] PYRIDIN 2 YL} [3 (4 METHYL PIPERAZIN 1 YL) PHENYL] AMINE; ANTINEOPLASTIC AGENT; CEP 33779; JANUS KINASE 2; JANUS KINASE 2 INHIBITOR; N [3 [(1,1 DIOXIDOTHIOMORPHOLIN 4 YL)METHYL]PHENYL] 8 [4 (METHYLSULFONYL)PHENYL][1,2,4]TRIAZOLO[1,5 A]PYRIDIN 2 AMINE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

AMINO ACID SUBSTITUTION; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYCLIZATION; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG EFFICACY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; IMMUNE DEFICIENCY; IN VIVO STUDY; MOLECULARLY TARGETED THERAPY; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DOGS; HUMANS; JANUS KINASE 2; MICE; MICE, NUDE; MICROSOMES, LIVER; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PYRIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84862287729     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300248q     Document Type: Article

References (39)

1. Yu, H.; Jove, R. The STATs of Cancer-New Molecular Targets Come of Age Nature Rev. Cancer 2004, 4, 97-105
2. Dagvadorj, A.; Collins, S.; Jomain, J.-B.; Abdulghani, J.; Karras, J.; Zellweger, T.; Li, H.; Nurmi, M.; Alanen, K.; Mirtti, T.; Visakorpi, T.; Bubendorf, L.; Goffin, V.; Nevalainen, M. T. Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Janus Kinase-2-Signal Transducer and Activator of Transcription-5a/b Signaling Pathway Endocrinology 2007, 148, 3089-3101
3. Pardanani, A. JAK2 Inhibitor Therapy in Myeloproliferative Disorders: Rationale, Preclinical Studies and Ongoing Clinical Trials Leukemia 2008, 22, 22-30
4. Kortylewski, M.; Kujawski, M.; Wang, T.; Wei, S.; Zhang, S.; Pilon-Thomas, S.; Niu, G.; Kay, H.; Mule, J.; Kerr, W. G.; Jove, R.; Pardoll, D.; Yu, H. Inhibiting Stat3 Signaling in the Hematopoietic System Elicits Multicomponent Antitumor Immunity Nature Med. 2005, 11, 1314-1321
5. Nefedova, Y.; Gabrilovich, D. I. Targeting of Jak/STAT Pathway in Antigen Presenting Cells in Cancer Curr. Cancer Drug Targets 2007, 7, 71-77
6. Lin, W.-W.; Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer J. Clin. Invest. 2007, 117, 1175-1183
7. Pardanani, A. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials Leukemia 2008, 22, 23-30
8. Marotta, L. L. C.; Almendro, V.; Marusyk, A.; Shipitsin, M.; Schemme, J.; Walker, S. R.; Bloustain-Qimron, N.; Kim, J. J.; Choudhury, S. A.; Maruyama, R.; Wu, Z.; Gönen, M.; Mulvey, L. A.; Bessarabova, M. O.; Huh, S. J.; Silver, S. J.; Kim, S. Y.; Park, S. Y.; Lee, H. E.; Anderson, K. S.; Richardson, A. L.; Nikolskaya, T.; Nikolsky, Y.; Liu, X. S.; Root, D. E.; Hahn, W. C.; Frank, D. A.; Polyak, K. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24- stem cell-like breast cancer cells in human tumors J. Clin. Invest. 2011, 121, 2723-2735
9. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sundarsanam, S. The Protein Kinase Complement of the Human Genome Science 2002, 298, 1912
10. Li, H.; Ahonen, T. J.; Alanen, K.; Xie, J.; LeBaron, M. J.; Pretlow, T. G.; Ealley, E. L.; Zhang, Y.; Nurmi, M.; Singh, B.; Martikainen, P. M.; Nevalainen, M. T. Activation of Signal Transducer and Activator of Transcription 5 in Human Prostate Cancer is Associated with High Histological Grade Cancer Res. 2004, 64, 4774-4782
11. Tan, S.-H.; Nevalainen, M. T. Signal Transducer and Activator of Transcription 5A/B in Prostate and Breast Cancers Endocr.-Relat. Cancer 2008, 15, 367-390
12. Quintas-Cardama, A.; Kantarjian, H.; Cortes, J.; Verstovsek, S. Janus Kinase Inhibitors for the Treatment of Myeloproliferative Neoplasias and Beyond Nature Rev. Drug Discovery 2011, 10, 127-140
13. Borie, D. C.; Si, M.-S.; Morris, R. E.; Reitz, B. A.; Changelian, P. S. JAK3 inhibition as a new concept for immune suppression Curr. Opin. Invest. Drugs 2003, 4, 1297-1303
14. O'Shea, J. J.; Pesu, M.; Borie, D. C.; Changelian, P. S. A New Modality for Immunosuppression: Targeting the JAK/STAT Pathway Nature Rev. Drug Discovery 2004, 4, 555-564
15. Flex, E.; Petrangeli, V.; Stella, L.; Chiaretti, S.; Hornakova, T.; Knoops, L.; Ariola, C.; Fodale, V.; Clappier, E.; Paoloni, F.; Martinelli, S.; Fragale, A.; Sanchez, M.; Tavolaro, S.; Messina, M.; Cazzaniga, G.; Camera, A.; Pizzolo, G.; Tornesello, A.; Vignetti, M.; Battistini, A.; Cave, H.; Gelb, B. D.; Renauld, J.-C.; Biondi, A.; Constantinescu, S. N.; Foa, R.; Tartaglia, M. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia J. Exp. Med. 2008, 205, 751-758
16. Minegishi, Y.; Saito, M.; Morio, T; Watanabe, K.; Agematsu, K.; Tsuchiya, S.; Takada, H.; Hara, T.; Kawamura, N.; Ariga, T.; Kaneko, H.; Konda, N.; Tsuge, I.; Yachie, A.; Sakiyama, Y.; Iwata, T.; Bessho, F.; Ohishi, T.; Joh, K.; Imai, K.; Kogawa, K.; Shinohara, M.; Fujieda, M.; Wakiguchi, H.; Pasic, S.; Abinun, M.; Ochs, H. D.; Renner, E. D.; Jansson, A.; Belohradsky, B. H.; Metin, A.; Shimizu, N.; Mizutani, S.; Miyawaki, T.; Nonoyama, S.; Karasuyama, H. Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity Immunity 2006, 25, 745-755
17. Tyner, J. W.; Bumm, T. G.; Deininger, J.; Wood, L.; Aichberger, K. J.; Loriaux, M. M.; Druker, B. J.; Burns, C. J.; Fantino, E.; Deininger, M. W. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms Blood 2010, 115, 5232-5240
18. Pardanani, A.; Gotlib, J. R.; Jamieson, C.; Cortes, J. E.; Talpaz, M.; Stone, R. M.; Silverman, M. H.; Gilliland, D. G.; Schorr, J.; Tefferi, A. Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis J. Clin. Oncol. 2011, 29, 789-796
19. 14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans Drug Metab. Dispos. 2010, 38, 2023-2031
20. Ruxolitinib was granted approval by the United States Food and Drug administration on November 16, 2011,: http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm280102.htm.
21. Hevdat, M.; Huszar, D.; Herrmann, A.; Gozgit, J. M.; Schroeder, A.; Sheehy, A.; Buettner, R.; Proia, D.; Kowolik, C. M.; Xin, H.; Armstrong, B.; Bebernitz, G.; Weng, S.; Wang, L.; Ye, M.; McEachern, K.; Chen, H.; Morosini, D.; Bell, K.; Alimzhanov, M.; Ioannidis, S.; McCoon, P.; Cao, Z. A.; Yu, H.; Jove, R.; Zinda, M. The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors Cancer Cell 2009, 16, 487-497
22. Hexner, E. O.; Serdikoff, C.; Jan, M.; Swider, C. R.; Robinson, C.; Yang, S.; Angeles, T.; Emerson, S. G.; Carroll, M.; Ruggeri, B.; Dobrzanski, P. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders Blood 2008, 111, 5663-5671
23. William, A. D.; Lee, A. C.-H.; Blanchard, S.; Poulsen, A.; Teo, E. L.; Nagaraj, H.; Tan E. Chen, D.; Williams, M.; Sun, E. T.; Goh, K. C.; Ong, W. C.; Goh, S. K.; Hart, S.; Jayaraman, R.; Pasha, M. K.; Ethirajulu, K.; Wood, J. M.; Dymock, B. W. Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19- dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5, 8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus 2/Fms-like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma J. Med. Chem. 2011, 54, 4638-4658
24. Nettekoven, M.; Püllmann, B.; Schmitt, S. Synthetic Access to 2-Amido-5-aryl-8-methoxy-triazolopyridine and 2-Amido-5-morpholino-8-methoxy- triazolopyridine Derivatives as Potential Inhibitors of the Adenosine Receptor Subtypes Synthesis 2003, 1649-1652
25. Zificsak, C. A.; Gingrich, D. E.; Breslin, H. J.; Dunn, D. D; Milkiewicz, K. L.; Theroff, J. P.; Thieu, T. V.; Underiner, T. L.; Weinberg, L. R.; Aimone, L. D.; Albom, M. S.; Mason, J. L.; Saville, L.; Husten, J.; Angeles, T. S.; Finn, J. P.; Jan, M.; O'Kane, T. M.; Dobrzanski, P.; Dorsey, B. D. Optimization of a novel kinase inhibitor scaffold for the dual inhibition of JAK2 and FAK kinases Bioorg. Med. Chem. Lett. 2012, 22, 133-137
26. Weinberg, L. R.; Albom, M. S.; Angeles, T. S.; Breslin, H. J.; Gingrich, D. E.; Huang, Z.; Lisko, J. G.; Mason, J. L.; Milkiewicz, K. L.; Thieu, T. T.; Underiner, T. L.; Wells, G. J.; Wells-Knect, K. J.; Dorsey, B. D. 2,7-Pyrrolo[2,1- f ][1,2,4]triazines as JAK2 inhibitors: modification of target structure to minimize reactive metabolite formation Bioorg. Med. Chem. Lett. 2011, 21, 7325-7330
27. Potts, K. T.; Burton, H. R.; Bhattacharyya, J. Derivatives of s -Triazolo[1,5-a]pyridine Ring System J. Org. Chem. 1966, 31, 260-265
28. Potts, K. T.; Burton, H. R.; Roy, S. K. Reactions of the s -Triazolo[4,3- a ]pyridine Ring System J. Org. Chem. 1966, 31, 265-273
29. Potts, K. T.; Surapaneni, C. R. 1,2,4-Triazoles. XXV. The Effect of Pyridine Substitution on the Isomerization of s -Triazolo[4,3- a ]pyridines into s -Triazolo[1,5- a ]pyridines J. Heterocycl. Chem. 1970, 7, 1019-1027
30. Verček, B.; Ogorevc, B.; Stanovnik, B.; Tišler, M. Cyanoamino Compounds in Synthesis: Syntheses of Some Heterocycles Monatsch. Chem. 1983, 114, 789-798
31. Bell, B. M.; Fanwick, P. E.; Graupner, P. R.; Roth, G. A. Application of the Tisler Triazolopyrimidine Cyclization to the Synthesis of a Crop Protection Agent and an Intermediate Org. Process Res. Dev. 2006, 10, 1167-1171
32. Swinnen, D.; Jorand-Lebrun, C.; Grippi-Vallotton, T.; Muzerelle, M.; Royle, A.; Macritchie, J; Hill, R.; Shaw, J. P. Preparation of triazolopyridines as apoptosis signal-regulating kinase (ASK) inhibitors for treatment of autoimmune, inflammatory, cardiovascular, and/or neurodegenerative diseases. Patent WO2009/027283A1, 2009.
33. 9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 4907-4912
34. Shakespeare, W. C.; Metcalf, C. A.; Sawyer, T. K.; Wang, Y.; Sundaramoorthi, R.; Dalgarno, D. C.; Bohacek, R.; Weigele, M. Substituted Purine Derivatives. Patent WO2005/009348A2, 2005.
35. Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant, P.; Atteridge, C. E.; Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P. T.; Faraoni, R.; Floyd, M.; Hunt, J. P.; Lockhart, D. J.; Milanov, Z. V.; Morrison, M. J.; Pallares, G.; Patel, H. K.; Pritchard, S.; Wodicka, L. M.; Zarrinkar, P. P. A Quantitative Analysis of Kinase Inhibitor Selectivity Nature Biotechnol. 2008, 26, 127
36. Cochet, O.; Frelin, C.; Peyron, J.-F.; Imbert, V. Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival Cell. Signalling 2006, 18, 449-455
37. Stump, K. L.; Lu, L. D.; Dobrzanski, P.; Serdikoff, C.; Gingrich, D. E.; Dugan, B. J.; Angeles, T. S.; Albom, M. S.; Ator, M. A.; Dorsey, B. D.; Ruggeri, B. A.; Seavey, M. M. A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis Arthritis Res. Ther.. 2011, 13, R68
38. Seavey, M. M.; Lu, L. D.; Stump, K. L.; Wallace, N. H; Hockeimer, W.; O'Kane, T. M.; Ruggeri, B.; Dobrzanski, P. Therapeutic Efficacy of CEP-33779, a Novel Selective JAK2 Inhibitor, in a Mouse Model of Colitis-induced Colorectal Cancer Mol. Cancer Ther. 2012, 11, 984-993
39. Mason, J., L.; Holskin, B. P.; Murray, K. A.; Meyer, S. L.; Ator, M. A.; Angeles, T. S. Modification of CellSensor Irf1-bla TF-1 and Irf1-bla HEL Assays for Direct Comparison of Wild-type JAK2 and JAK2 V617F Inhibition Assay Drug Dev. Technol. 2011, 9, 311-318